Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands.
BACKGROUND
Polybrominated diphenyl ethers (PBDEs) are widely found in the environment and are suspected endocrine disruptors. We previously identified six hydroxylated metabolites of PBDE (OH-PBDEs) in treated mice.


OBJECTIVE
We tested the hypothesis that OH-PBDEs would interact with and alter activity of estrogen receptor-alpha (ER-alpha).


METHODS
We tested estrogenicity using two assays: 3H-estradiol (3H-E2) displacement from recombinant ER-alpha and induction of reporter gene (ERE-luciferase) in cultured cells. We incubated the PBDE mixture DE-71 with rat liver microsomes and tested the resultant metabolite mixture for estrogenic activity. We also determined relative estrogenic potential of individual hydroxylated PBDE congeners.


RESULTS
Reporter gene activity was increased by DE-71 that had been subjected to microsomal metabolism. DE-71 did not displace E2 from ER-alpha, but all six of the OH-PBDE metabolites did. para-Hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ER-alpha compared with ortho-hydroxylated PBDEs, and one produced a maximal effect 30% higher than that produced by E2. Coadministration of E2 and DE-71, or certain of its metabolites, yielded reporter activity greater than either chemical alone. Two ortho-OH-PBDEs were antiestrogenic in the reporter assay.


CONCLUSIONS
The observations--that the DE-71 mixture did not displace 3H-E2 from ER-alpha while the hydroxylated metabolites did-suggest that the weak estrogenic effects of DE-71 are due to metabolic activation of individual congeners. However, the behavior of DE-71 and its metabolites, when co-administered with E2, suggest a secondary, undetermined mechanism from classical ER-alpha activation.
Mercado-Feliciano
Minerva
M
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5121, USA.
Bigsby
Robert M
RM
D000818:Animals; D001711:Biotransformation; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D017930:Genes, Reporter; D055768:Halogenated Diphenyl Ethers; D006900:Hydroxylation; D008024:Ligands; D008862:Microsomes, Liver / Q000187:drug effects; D010647:Phenyl Ethers / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism
D047628:Estrogen Receptor alpha; D055768:Halogenated Diphenyl Ethers; D008024:Ligands; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; D011994:Recombinant Proteins; C086401:pentabromodiphenyl ether